title: Cytochrome P450 CYP1B1 interacts with 8-methoxypsoralen (8-MOP) and influences psoralen-ultraviolet A (PUVA) sensitivity.
abstract: BACKGROUND
  There are unpredictable inter-individual differences in sensitivity to psoralen-UVA (PUVA) photochemotherapy, used to treat skin diseases including psoriasis. Psoralens are metabolised by cytochrome P450 enzymes (P450), and we hypothesised that variability in cutaneous P450 expression may influence PUVA sensitivity. We previously showed that P450 CYP1B1 was abundantly expressed in human skin and regulated by PUVA, and described marked inter-individual differences in cutaneous CYP1B1 expression.
  
  
  OBJECTIVE
  We investigated whether CYP1B1 made a significant contribution to 8-methoxypsoralen (8-MOP) metabolism, and whether individuality in CYP1B1 activity influenced PUVA sensitivity.
  
  
  METHODS
  We used E. coli membranes co-expressing various P450s and cytochrome P450 reductase (CPR) to study 8-MOP metabolism and cytotoxicity assays in CYP1B1-expressing mammalian cells to assess PUVA sensitivity.
  
  
  RESULTS
  We showed that P450s CYP1A1, CYP1A2, CYP1B1, CYP2A6 and CYP2E1 influence 8-MOP metabolism. As CYP1B1 is the most abundant P450 in human skin, we further demonstrated that: (i) CYP1B1 interacts with 8-MOP (ii) metabolism of the CYP1B1 substrates 7-ethoxyresorufin and 17-β-estradiol showed concentration-dependent inhibition by 8-MOP and (iii) inhibition of 7-ethoxyresorufin metabolism by 8-MOP was influenced by CYP1B1 genotype. The influence of CYP1B1 on PUVA cytotoxicity was further investigated in a Chinese hamster ovary cell line, stably expressing CYP1B1 and CPR, which was more sensitive to PUVA than control cells, suggesting that CYP1B1 metabolises 8-MOP to a more phototoxic metabolite(s).
  
  
  CONCLUSIONS
  Our data therefore suggest that CYP1B1 significantly contributes to cutaneous 8-MOP metabolism, and that individuality in CYP1B1 expression may influence PUVA sensitivity.
authors.affiliation: Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, United Kingdom ; School of Contemporary Science, University of Abertay Dundee, Dundee, United Kingdom.
authors.forename: Yusuf Y
authors.initials: YY
authors.lastname: Deeni
authors.forename: Sally H
authors.initials: SH
authors.lastname: Ibbotson
authors.forename: Julie A
authors.initials: JA
authors.lastname: Woods
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.forename: Gillian
authors.initials: G
authors.lastname: Smith
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D016466:CHO Cells; D003412:Cricetulus; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D005363:Ficusin / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D008730:Methoxsalen / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D014467:Ultraviolet Therapy / Q000379:methods
chemical_list: D010078:Oxazines; D004958:Estradiol; C007649:ethoxyresorufin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D005363:Ficusin; D008730:Methoxsalen